This application requests funding to continue multidisciplinary studies of mechanisms of airway remodeling in chronic inflammation. Drs. Basbaum, Caughey, Killeen, and McDonald have collaborated closely in this Program Project Grant for many years and will continue their efforts to understand the cellular and molecular pathophysiology of airway remodeling. They will focus on how changes in epithelial and inflammatory cells, blood vessels, lymphatics, and proteases contribute to airway remodeling. Using state-of-the-art molecular, cellular, morphological, immunological, and genetic approaches, the multidisciplinary team will approach the problem in four ways. Project 1, led by Dr. Basbaum, will explore mechanisms of pathological down-growth of surface epithelium to form submucosal glands, focusing on the roles of lymphocytes and the metalloproteinase inducer EMMPRIN in gland bud formation. Project 2, led by Dr. Caughey, will investigate roles of extracellular proteases from airway epithelial cells, mast cells, and inflammatory cells in remodeling of the airway microvasculature and epithelium, emphasizing in vitro explorations of the molecular behavior and targets of proteases and in vivo studies of selected proteases and their targets in genetically engineered mice. Project 3, led by Dr. Killeen, will examine molecular mechanisms whereby T and B lymphocytes cooperate in triggering antibody-mediated remodeling of the airway microvasculature and epithelium and will identify the mediators involved. Project 4, let by Dr. McDonald, will examine the mechanisms, consequences, and reversibility of angiogenesis and lymphangiogenesis to explore the gate-keeper function of the microvasculature in sustaining chronic airway inflammation and the role of defects in lymphatic growth in mucosal edema. Novel transgenic mouse models and mice with chronic airway inflammation from Mycoplasma pulmonis infection will be used in many investigations. To facilitate these studies, each of the projects will be supported by a Mouse Genotyping and Infection Core, led by Dr. Killeen. The Program Project team has a long tradition of collaborative research and use of multidisciplinary strategies for studying airway inflammation and remodeling. Collectively, their powerful armory of experience and skills in cellular and molecular biology, enzymology, microscopic imaging, and immunology will be used with innovative biochemical, in vivo model systems to solve the mysteries of airway remodeling in chronic disease. Understanding the causes of remodeling will suggest new strategies to prevent or reverse the long lasting changes in the airway wall typical of asthma, bronchitis, cystic fibrosis, and other chronic inflammatory airway diseases affecting a growing share of population.